This invention is directed to new chemical compounds, especially useful as inhibitors of lipoxygenase enzyme systems. Lipoxygenase controls the biosynthesis of the class of compounds known as leukotrienes. Inhibition of lipoxygenase therefore prevents or diminishes the adverse effects of the leukotrienes in a human subject.
The leukotrienes are a novel group of biologically active mediators derived from arachidonic acid through the action of lipoxygenase enzyme systems. The leukotrienes play an important role in inducing allergic reactions, such as asthma, allergic bronchitis or allergic rhinitis in man. One of the leukotrienes (B.sub.4) contributes to both inflammation and allergic reactions in man.
There are two groups of leukotrienes derived from the common unstable precursor Leukotriene A.sub.4. The first of these are the peptido-lipid leukotrienes, the most important being Leukotrienes C.sub.4 and D.sub.4. These compounds collectively account for the biological activity known as slow reacting substances of anaphylaxis. They are potent smooth muscle contracting agents, particularly on respiratory smooth muscle but also on other tissues (e.g., gall bladder). In addition, they promote mucous production, modulate vascular permeability changes and are potent inflammatory agents in human skin.
The most important compound in the second group of leukotrienes is leukotriene B.sub.4, a dihydroxy fatty acid derived from leukotriene A.sub.4. This compound is a potent chemotactic agent for neutrophils and eosinophils. When injected in vivo, in addition to promoting the accumulation of leukocytes, leukotriene B.sub.4 is also a potent hyperalgesic agent and can modulate vascular permeability changes through a neutrophil dependent mechanism. Both groups of leukotrienes are formed following oxygenation of arachidonic acid through the action of the 5-lipoxygenase enzyme. See D. Bailey and F. Casey, Ann. Rpts. Med. Chem. 17 203 (1982).
Leukotrienes can also mediate other diseases. These include psoriasis, atopic dermatitis, gouty arthritis and gall bladder spasms. In addition, they may have a role in cardiovascular disease because leukotrienes C.sub.4 and D.sub.4 act as coronary and cerebral arterial vasoconstrictors and these compounds may also have negative ionotropic effects on the myocardium. In addition, leukotrienes are important mediators of inflammatory diseases through their ability to modulate leukocyte and lymphocyte function.